A minimal model for calcium signal generated by tyrosine kinase and G protein linked receptors; a stochastic computer simulation with CALSIM.
A software was designed to simulate the calcium signal following hormone or growth factor stimulation in epithelial cells. The software written in C runs on a PC under Windows environment. It is based on a Markov process where the dynamic of the system is characterised by phenomenological transition probabilities. Moreover a minimal model is proposed to analyse the role of plasma channels and IP3 receptors, together with the opposite action of the CaATPase pumps, in the cytosolic and endoplasmic reticulum (ER) calcium signal control. The simulation is applied on the calcium response following stimulation by carbacol (protein G coupled receptors) or epidermal growth factor (tyrosine kinase type receptors) in A431 epithelial cells. The experimental calcium signals can be grouped in three classes; a spike and a return to the basal level (signal A), a spike and a decrease to a plateau level (signal B) or a slow increase to a plateau (signal C). Epidermal growth factor induces signal A and B while carbacol gives signal B and C. When a 'pseudo' steady state is reached oscillations occur. Computer simulations show that signal A can result from the activation of IP3 receptors while signal C would result from the activation of the plasma channels; signal B appears as the additive contribution of both channels, while oscillations are compatible with a calcium induced calcium release mechanism. Simulations suggest that the calcium dynamic in the ER is a mirror of cytosolic calcium but that a simple way to produce similar calcium elevation in these two compartments is to activate plasma channels. Implications of such a mechanism is discussed.
Seghieri
P
P
Laboratoire de Cancérologie Expérimentale, INSERM CJF 9311, IFR J. Roche, Faculté de Médecine Nord, Marseille, France.
Dussert
C
C
Palmari
J
J
Berthois
Y
Y
Martin
P M
PM
Penel
C
C
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000465:Algorithms; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000187:drug effects / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003198:Computer Simulation; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007295:Inositol Phosphates / Q000378:metabolism; D016623:Ion Pumps / Q000187:drug effects / Q000378:metabolism; D008390:Markov Chains; D008954:Models, Biological; D008956:Models, Chemical; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012984:Software; D013269:Stochastic Processes; D014407:Tumor Cells, Cultured
D015220:Calcium Channels; D007295:Inositol Phosphates; D016623:Ion Pumps; D011956:Receptors, Cell Surface; D004815:Epidermal Growth Factor; D002217:Carbachol; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins; D000252:Calcium-Transporting ATPases; D002118:Calcium